Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity

Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity

Cell, Volume 154, Issue 1, Pages 61-74, Publication Date 3 July 2013
Copyright ? 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2013.06.005

Christine?L. Chaffer

Nemanja?D. Marjanovic

Tony Lee

George Bell

Celina?G. Kleer

Ferenc Reinhardt

Ana?C. D?Alessio

Richard?A. Young

Robert?A. Weinberg

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA

University of Michigan Medical School, Department of Pathology, Ann Arbor, MI 48109, USA

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

Ludwig MIT Center for Molecular Oncology, Cambridge, MA 02139, USA

Corresponding author

These authors contributed equally to this work

Summary

The recent discovery that normal and neoplastic epithelial cells re-enter the stem cell state raised the intriguing possibility that the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs) but from their proclivity to generate new CSCs from non-CSC populations. Here, we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC state. The observed cell plasticity is dependent on ZEB1, a key regulator of the epithelial-mesenchymal transition. We find that plastic non-CSCs maintain the ZEB1 promoter in a bivalent chromatin configuration, enabling them to respond readily to microenvironmental signals, such as TGF?. In response, the ZEB1 promoter converts from a bivalent to active chromatin configuration, ZEB1 transcription increases, and non-CSCs subsequently enter the CSC state. Our findings support a dynamic model in which interconversions between low and high tumorigenic states occur frequently, thereby increasing tumorigenic and malignant potential.

Source: http://www.cell.com/abstract/S0092-8674(13)00707-1

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